A great deal of research is currently underway to develop treatments and cures for viral infections in humans and in animals. Notably the incidence of AIDS and ARC in humans is increasing at an alarming rate. The five year survival rate for those with AIDS is dispiriting and AIDS patients, whose immune systems have been seriously impaired by the infection, suffer from numerous opportunistic infections including Kaposi's sarcoma and Pneumocystis carninii pneumonia. No cure is known and current treatments are largely without adequate proof of efficacy and have numerous untoward side effects. Fear of the disease has resulted in social ostracism of and discrimination against those having or suspected of having the disease.
Retroviruses are a class of ribonucleic acid (RNA) viruses that replicate by using reverse transcriptase to form a strand of complementary DNA (cDNA) from which a double stranded, proviral DNA is produced. This proviral DNA is then randomly incorporated into the chromasomal DNA of the host cell making possible viral replication by later translation of the integrated DNA containing the viral genome.
Many of the known retroviruses are oncogenic or tumor causing. Indeed the first two human retroviruses discovered, denoted human T-cell leukemia virus I and II or HTLV-I and II, were found to cause rare leukemias in humans after infection of T-lymphocytes. The third such human virus to be discovered, HTLV-III, now referred to as HIV, was found to cause cell death after infection of T-lymphocytes, specifically the CD4.sup.+ subpopulation, and has been identified as the causative agent of acquired immune deficiency syndrome (AIDS) and AIDS related complex (ARC).
Retroviruses have, in addition to the usual viral capsid, an outer membrane of lipid and glycoprotein, similar to the membrane of ordinary cells. Indeed the lipid of the retroviral membrane is probably derived directly from the membrane of a previously infected host cell, however, the glycoprotein of the viral membrane is unique to the virus itself and is coded for by the viral genome. Infection of a host cell by a retrovirus initially relies on the interaction of various receptors on the host cell surface with the glycoprotein membrane envelope of the virus. Subsequently the virus and cell membranes fuse and the virion contents are released into the host cell cytoplasm. The glycoprotein envelope of the retroviruses plays an important role in both the initial interaction of the virion and the host cell and in the later fusion of the viral and host cell membranes.
In addition to the retroviruses, certain other viruses are coated or enveloped by a glycoprotein layer as well. Such viruses include the herpes simplex viruses (HSV), the influenza viruses, cytomegloviruses (CMG), and others.
Infection of human CD4.sup.+ cells by HIV has been shown to involve binding of the HIV gp120 surface protein to a receptor on the surface of the CD4.sup.+ cells, the CD4 receptor. Recently it has been observed that binding of HIV to CD4.sup.+ cells is accompanied by phosphorylation of CD4 and it has been suggested that this phosphorylation may be protein kinase C (PKC) mediated. Fields, et al., Nature, Vol. 333, 19 May 1988. Experiments indicate that the presence of the PKC inhibitor, 1,5-isoquinolinesulphonyl-2-methylpiperazine dihydrochloride, does not interfere with HIV cell surface binding but causes an accumulation of virus particles at the cell surface and inhibition of viral infectivity, thus supporting the concept that phosphorylation, subsequent to binding, is necessary for infectivity. Applicants have discovered that PKC mediated phospharglation is important in infectivity of Moloney Murine Leukemia virus (MoLV) as well, and applicants suggest that PKC mediated phosphorylation is an important step in host binding infectivity of enveloped viruses in general.
Applicants have determined that certain pyridinyloxazole-2-ones having PKC inhibiting activity are useful in the treatment of various enveloped virus infections including in the treatment of AIDS and ARC resulting from infection by HIV or other retroviruses.